Diabetes is a metabolic disorder, with global organ system pathology arising in great part to micro- & macrovascular disease. Macrovascular disease initiates at pre-clinical phases of impaired glucose metabolism, & rate-limiting repair of diseased matrix may prolong clinical responses. The ability to cure or substantially reverse diabetic macrovascular disease (DMAC) represents an unmet clinical need. A better understanding of the pathobiology during initiation and progression is required. DMAC is a vascular inflammatory state affecting adventitial, medial, intimal, and valvular compartments. Calcification is a key component of DMAC that reduces vascular compliance, and increases mortality and risk for lower extremity amputation. Medial, intimal, and valve calcification are more prevalent in diabetic patients, worsened by progressive renal insufficiency. Paracrine & endocrine signals act on vascular myofibroblasts to regulate an early osteogenic phase of vascular calcification. A pro-osteogenic gene regulatory program - a "feed-forward" BMP2-Msx2- Wnt signaling cascade - is activated in aortic myofibroblasts by diabetes and dyslipidemia (LDLR-/- mice). Surprisingly, the bone anabolic agent PTH(1-34) suppresses vascular calcification while enhancing orthotopic bone formation. We now extend our studies of vascular calcification as regulated by endocrine & paracrine cues. Under Aim 1, we examine the role for the cytokine osteopontin in inhibition & potential reversal of vascular calcification by PTH{1-34). We test if PTH(1-34) inhibits the proliferative expansion and osteogenic commitment of vascular mesenchymal progenitors in vivo. Under Aim 2, SM22-PTH1 R(H223R) transgenic mice will test whether vascular myofibroblast PTH1R activation (a) suppresses vascular calcification; and (b) inhibits vascular Msx2-Wnt signaling cascades in vivo as it does in vitro. Under Aim 3, we test whether the enhanced aortic Msx2-Wnt signaling in our Msx2 transgenic mice pre-disposes animals to vascular calcification as predicted from in vitro studies, either alone or in synergy with vascular BMP2.